ABSTRACT
BACKGROUND: This phase I cohort study investigated aflibercept (vascular endothelial growth factor (VEGF) trap) plus docetaxel and cisplatin in patients with advanced solid tumours. METHODS: Patients received intravenous aflibercept 4, 5, or 6 mg kg(-1) with docetaxel and cisplatin (75 mg m(-2) each) on day 1 of a 3-week cycle until progressive disease or unacceptable toxicity. Primary objectives were determining cycle 1 dose-limiting toxicities (DLTs) and the aflibercept recommended phase II trial dose (RP2D) for this combination. RESULTS: During the dose-escalation phase (n=16), there were two DLTs of febrile neutropenia (at 4 and 5 mg kg(-1)). Granulocyte colony-stimulating factor prophylaxis was subsequently recommended. The RP2D of aflibercept was established at 6 mg kg(-1) and administered to 14 additional patients. The most frequent grade 3/4 adverse events (AEs) were neutropenia (43.3%), stomatitis (20.0%), asthenia/fatigue (20.0%), and hypertension (16.7%). All-grade AEs associated with VEGF blockade included epistaxis (83.3%), dysphonia (70.0%), proteinuria (53.3%), and hypertension (50.0%). There were five partial responses (16.7%) and 18 cases of stable disease (60.0%) (lasting >3 months in 10 patients). There were no pharmacokinetic (PK) interactions between the three drugs. CONCLUSION: Aflibercept 6 mg kg(-1) with docetaxel and cisplatin 75 mg m(-2) every 3 weeks is the RP2D based on tolerability, antitumour activity, and PKs.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cisplatin/administration & dosage , Neoplasms/drug therapy , Recombinant Fusion Proteins/administration & dosage , Taxoids/administration & dosage , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Docetaxel , Drug Administration Schedule , Fatigue/chemically induced , Female , Humans , Male , Middle Aged , Neutropenia/chemically induced , Receptors, Vascular Endothelial Growth FactorABSTRACT
A phase II study was conducted to determine the efficacy and the safety of docetaxel combined with vinorelbine as first-line chemotherapy in patients with metastatic or unresectable non-small cell lung cancer (NSCLC). 39 patients, median age 54 years (range: 35-69), with stage IIIB (5 patients; 13%) or IV (34 patients; 87%) NSCLC were treated with 75 mg/m(2) docetaxel given intravenously (i. v.) over 1 h on day 1 and with 20 mg/m(2) vinorelbine given i.v. over 15 to 30 min on days 1 and 5. Cycles were repeated every 3 weeks. 9 of the 39 patients had a partial response (overall response rate 23.1%, 95% confidence interval (CI): 11.1-39.3%) with a median duration of response of 20 weeks (95% CI; 17-30). The median survival was 40 weeks (95% CI: 21-49 weeks) with a 1-year survival rate of 31% in the intent-to-treat population. Neutropenia grade IV occurred in 33 patients (92%). 16 patients (41%) experienced febrile neutropenia with a concomitant stomatitis in 9 patients (23%). One patient died due to febrile neutropenia associated with a grade 4 stomatitis and 1 patient due to a septicaemia concomitant with a grade 4 neutropenia. Although the combination of docetaxel and vinorelbine is feasible, the efficacy does not seem to be improved compared with single-agent docetaxel or vinorelbine and the rate of febrile neutropenia is unacceptable in this population with incurable disease. Therefore, different doses and/or schedules are to be explored.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Taxoids , Adult , Aged , Docetaxel , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Neutropenia/chemically induced , Paclitaxel/administration & dosage , Paclitaxel/analogs & derivatives , Survival Rate , Treatment Outcome , Vinblastine/administration & dosage , Vinblastine/analogs & derivatives , VinorelbineABSTRACT
The objective of this study was to evaluate a regimen of full doses of docetaxel and cisplatin, using an alternating schedule, as first-line therapy for patients with inoperable non-small cell lung cancer (NSCLC). The standard concomitant schedule does not allow full doses of both drugs to be administered. We wanted to see if there was an advantage to be gained by administering full doses of both docetaxel and cisplatin, using a different schedule. Docetaxel 100 mg/m2 was given once every 6 weeks from week 1 and cisplatin (120 mg/m2 for two doses and 100 mg/m2 thereafter) once every 6 weeks from week 4, for six cycles (three docetaxel and three cisplatin). Thirty-six of the 44 patients enrolled were evaluable for efficacy. Forty-eight percent of the patients had good (KPS 90-100%) performance status. A median of five cycles was administered, for which no dose reductions were necessary. There were 13 of 36 partial responses (36%; 95% CI 21-54%) and 15 of 36 patients achieved stable disease (42%). The median duration of response was 10.5 months, the median time to progression was 4.5 months and the median survival was 9 months. The 1 and 2 year survival rates were 39 and 16%, respectively. The most frequent grade 3-4 toxicities were nausea (23% of patients), vomiting (18%) and neutropenia (77%). Infections were also common, but not severe. The alternating schedule produced response, toxicity and survival figures that compared favorable with those using the concomitant schedule. This study could serve as a model for future studies of non-cisplatin-containing regimens, in which full doses of docetaxel could alternate with full doses of other new agents active against NSCLC.
